Angiogenesis is an essential component of tumor growth and metastasis. As reviewed by Folkman (1985), the growth of solid tumors is dependent on angiogenesis. Typically tumors do not grow beyond a size of 2-3 mm unless they are able to stimulate the growth of new capillaries from the existing vascular network. Additionally, the new blood vessels provide an essential entry route to the vasculature for metastasis of tumor cells. Cell division in endothelial cells is slow, with a turnover time of years rather than days or hours (Denekamp, 1984).
However, vascular endothelial cells undergo rapid proliferation with turnover times of a few days during the growth of new capillaries. Angiogenesis-dependent diseases such as diabetic retinopathy, psoriasis, arthritis, hemangiomas and tumor growth and metastasis are characterized by uncontrolled growth of capillary blood vessels. The most striking example of uncontrolled angiogenesis is associated with tumor growth (Folkman, 1985).
Accordingly, the search for angiogenesis inhibitors was stimulated by the concept of "antiangiogenic therapy". In its simplest terms, antiangiogenic therapy sought a putative inhibitor of blood vessel growth in the believe that such an inhibitor might be therapeutic by limiting tumor growth and further such an inhibitor would be non-toxic because angiogenesis is normally infrequent (Folkman, 1992). A number of different factors can stimulate angiogenesis in vivo. These angiogenic factors, such as basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and transforming growth factor .alpha. and .beta., can be released from the tumor cells themselves and by other cells such as macrophages and endothelial cells (Folkman, 1992).
The mechanisms by which tumors induce angiogenesis are very complex and involve many pathways, an angiogenesis inhibitor could be directed against any of the components of the angiogenic cascade. The identification of compounds that block neovascularization has a long standing interest. A number of inhibitory extracts have been prepared from avascular tissues, such as cartilage (Braunhut et al., 1989). One such method of treating tumors has been by the administration of suramin. However, it is believed that suramin may have adverse effects in large dosages.
Accordingly, a continuing need exists for agents that overcome the deficiencies of prior antiangiogenic compounds, including suramin. There is also a need for antiangiogenic agents that have a reduced toxicity to a recipient and increase inhibition of angiogenesis and tumorigenesis.